The present invention, in some embodiments thereof, relates to antiseptic compositions and uses thereof and, more particularly, but not exclusively, to antiseptic compositions which can be efficiently used in disinfecting surfaces such as bodily surfaces, and thus can be efficiently used, for example, in the treatment of infection-associated medical conditions such as acute and chronic wounds, burns, and surgical wounds.
Chronic wounds are characterized by an impaired healing process, a prolonged inflammatory stage, re-epithelization failure and defective extra-cellular matrix re-modeling. Cells accumulated within these wounds are senescent and their response to exogenous growth factors is reduced. The end result of the impaired healing process of the chronic wound is tissue breakdown, local necrosis and infection.
Management of wound bed is a multistep process necessary to achieve ultimate wound closure. Debridement, infection control, and wound closure are fundamental stages in the healing of chronic wounds.
In 2005, hospital acquired infections was ranked as the fourth-leading cause of death in the USA. It has been reported that approximately 10 million patients with traumatic wounds are treated in US emergency departments annually. Chronic wounds affect 1-3% of the entire population and include primarily venous leg ulcers, diabetic foot ulcers and pressure ulcers. Venous ulcers caused by chronic venous insufficiency are the most frequent (˜70%) among the non-healing chronic wounds.
The number of emergency cases in which the infection of a chronic wound leads to life-threatening complications is increasing along with the growth in the number of chronic wounds infected with microorganisms resistant to antibiotics. The presence of bacterial colonization is one of the most crucial factors in the pathogenesis of most chronic wounds, resulting in high bacterial counts in wound tissue and in inflammatory host response.
In infected chronic wounds, wound healing is delayed or even abrogated when infected with heavy bacterial burden. The reduction of bacterial load is crucial and should be carried out prior to the healing process. In order to optimize the wound healing process, treatment of underlying factors such as malnutrition and ischemia along with decreasing bacterial load is often necessary.
Infection of chronic wounds delays healing and usually causes deterioration in the condition of the chronic wound bed, which can also result in complete breakdown of the wound. Apart from the detrimental effect on wounds, infection can cause systemic effect, which in some cases can be fatal.
Bacterial contamination delays wound healing through several different mechanisms e.g., persistent production of inflammatory mediators resulting in a prolonged inflammatory response that contributes to host injury and delays the healing process. In addition, bacteria compete with host cells for nutrients and oxygen essential for the wound healing process. Wound infection can also lead to tissue hypoxia, interrupt the development of granulation tissue, reduce the number of fibroblasts and collagen production and damage re-epithelization. Addressing the question of infected wound cleansing is therefore a major objective of wound care and plays a critical role in wound management.
A large fraction of foot ulcers results from complication of diabetes mellitus. These lesions frequently become infected and are often accompanied by osteomyelitis. Most infections in these lesions are mild to moderate in severity and can be managed with appropriate wound care and oral antibiotic therapy. Some infections, however, penetrate to the fascia, muscle, joint and bone. In theses cases, the patients require hospitalization, parenteral antibiotic therapy and surgical procedures. In some cases, foot infections in patients with diabetes can be difficult to treat and therapeutic failure often leads to a lower-extremity amputation. In addition, diabetic foot infections caused by methicillin-resistant S. aureus (MRSA) are associated with delayed healing an in many cases with amputations.
Antiseptic agents are commonly used to prevent and treat wound infections. Unlike antibiotics which act selectively on specific microorganisms, the antiseptic agents have multiple targets and a broader spectrum of activity. Most of the practiced antiseptic agents have not been shown to clearly impede healing.
Among the commercially available antiseptic agents the most commonly used in clinical practice are iodine, chlorhexidine, alcohol, acetate, hydrogen peroxide, boric acid, silver nitrate, silver sulfadiazine and sodium hypochlorite. Their efficacy, however, seems to be limited in view of recently reported outbreaks associated with contaminated antiseptics [Weber et al. 2007, Antimicrob Agent Chemother 51: 4217-4224].
Silver compounds have been widely used as wound antiseptics to counter bacterial infections in chronic and acute wounds including burns [Burrell 2003, Ostomy Wound Manag 49:19-24; Ovington 2004, Ostomy Wound Manag 50:1S-15]. Silver is known to block the growth of gram-negative and gram-positive bacteria. Ionic silver kills microorganisms but it is non-cytotoxic to proliferating granulation tissue. Silver formulations appear to increase the rate and degree of microbial killing, decrease exudate formation and recently reported to affect bacterial biofilms.
The most commonly used silver compounds are silver sulfadiazine (SSD) and silver nitrate (AgNO3). Other commonly employed topical silver containing agents are nanocrystalline silver particles. Silver sulfadiazine (SSD) is usually used as a treatment for the prevention of infection in patients with burn wounds [Klasen 2000, Burns 26: 131-138]. Nanocrystalline silver releasing systems, e.g., Acticoat®[Tredget et al. 1998, J. Burn Care Rehabil. 19: 531-537] were developed in order to prolong its efficacy. Patients with infected chronic pressure ulcers were subjected to SSD and effective decreasing of the bacterial load were observed in all ulcers. SSD 1% cream significantly reduced venous ulcer, positively affecting wound cleansing and granulation tissue formation.
Silver nitrate was used first for the treatment of chronic wounds and ulcers [Klasen 2000, Burns 26: 131-138]. It was found to be effective against a wide range of bacterial flora especially against gram-negative bacteria. Nanocrystalline silver was incorporated later into wound dressings as a sustained release formulation for the treatment of acute and chronic wounds including burns [Voight et al. 2001, Wounds 13: B11-B21; Sondi and Salopek-Sondi 2004, J Colloid Interf Sci 275: 177-182; Parsons et al. 2005, Wounds, 17: 222-232].
Silver containing formulations for topical wound treatment are mostly based on silver containing wound dressing. The delivery and penetration of silver ions into the infected wound bed by such dressings is often limited by chemical reactions e.g. with chloride ions resulting in precipitation of inactive silver chloride, reducing the effective amount of antimicrobial silver ions reaching the targeted infected areas. Other drawbacks include silver affected coloration and local irritation.
In parallel with the common and excessive use of silver based topical treatments for wound management an increase in the number of reports on bacterial silver resistance was noticed [Silver 2003, FEMS Microbiology Reviews 27:341-353; Chopra 2007, J Antimicrobial Chemotherapy 59: 587-590].
Menthol is a natural monoterpene of plant origin, frequently used in dermatology as part of antipruritic, antiseptic, analgesic and/or cooling formulations. The molecular mechanisms underlying menthol contribution to these activities—and in particular to its antibacterial activity—were recently described [Patel, 2007, J Am Acad Dermatol 57: 873-878; Evrand 2001, Pharma Resear 18:943-949; Trombetta et al. 2005, Antimicrob Agent Chemother 49: 2474-2478; Schelz et al. 2006, Fiterapia 77: 279-285; Cristani et al. 2007, J Agri Food Chem 55: 6300-6308].
Hypertonic solutions are expected to add benefits to wound bed management by reduction of microbial load, enhanced exudate removal and impact on fluid circulation. Hypertonic saline solutions have been proven to be a very useful tool in neurosurgical practice.
Art of relevance include U.S. Pat. Nos. 5,643,589 and 5,562,643
Menthol has been described in the art as an antipruritic agent, antiseptic agent, analgesic and cooling agent, which can be used also in dermatological applications. Compositions comprising silver ions and menthol have also been described.
For example, The Merck Manual suggests combining menthol and silver in dermatological compositions in the chapter “Principles of Topical Dermatologic Therapy”. Silver is defined as an antiseptic agent and menthol is defined as an anti-pruriritic agent (anti-itching agent) therein.
Additional relevant art include International Patent Application No. PCT/IL2007/000015, U.S. Pat. No. 6,551,608, U.S. patent application Ser. No. 11/783,668 (Publication No. 20070255193) and U.S. patent application Ser. No. 10/535,961 (Publication No. 20060105000),
Antiseptic compositions comprising silver ions have also been disclosed in U.S. Pat. No. 5,607,683 and U.S. Pat. No. 6,093,414.
A continuous Streaming of Therapeutic solution (CST) is a new modality of chronic wound management developed by the present inventors, as well as others, and involves the continuous streaming of fresh doses of therapeutic solutions into the controlled wound environment. Streaming over chronic wounds allows for aseptic confinement of the wound, negative pressure therapy (pump-free), moist conditions, continuous cleansing and overall management of the wound bed. Such Continuous Streaming therapy has been disclosed, for example, in U.S. Pat. No. 7,364,565, to some of the present inventors.